Enantioselective CO2 Fixation Via a Heck-Coupling/Carboxylation Cascade Catalyzed by Nickel

Article abstract of DOI:10.1002/chem.202101082

A novel asymmetric nickel-based procedure has been developed in which CO₂ fixation is achieved as a second step of a truncated Heck coupling. For this, a new chiral ligand has been prepared and shown to achieve enantiomeric excesses up to 99 %. The overall process efficiently furnishes chiral 2,3-dihydrobenzofuran-3-ylacetic acids, an important class of bioactive products, from easy to prepare starting materials. A combined experimental and computational effort revealed the key steps of the catalytic cycle and suggested the unexpected participation of Ni(I) species in the coupling event.

Full text of DOI:10.1002/chem.202101082

Communication
doi.org/10.1002/chem.202101082
Chemistry—A European Journal
Enantioselective CO2 Fixation Via a Heck-
Coupling/Carboxylation Cascade Catalyzed by Nickel
Alessandro Cerveri,[a] Riccardo Giovanelli,[a] Davide Sella,[a] Riccardo Pedrazzani,[a]
Magda Monari,[a] Olalla Nieto Faza,[b] Carlos Silva López,*[b] and Marco Bandini*[a, c]
catalytic carboxylation reactions is still far from being fully
Abstract: A novel asymmetric nickel-based procedure has
been developed in which CO2 fixation is achieved as a
second step of a truncated Heck coupling. For this, a new
developed.[5]
In this context, the enantiopure 2,3-dihydrobenzofuran-3-
ylacetic acid scaffold A (Figure 1) is of pivotal importance in
chiral ligand has been prepared and shown to achieve
naturally occurring compounds.[6] However a direct and stereo-
enantiomeric excesses up to 99%. The overall process
selective catalytic approach to this motif has not been found
efficiently furnishes chiral 2,3-dihydrobenzofuran-3-ylacetic
yet.[7] In continuation with our research program focused on
acids, an important class of bioactive products, from easy to
CO2 fixation procedures[8a] and Ni-catalyzed cross-coupling
prepare starting materials. A combined experimental and
reactions,[8b–d] we envisioned the possibility to apply metal
computational effort revealed the key steps of the catalytic
catalyzed CO2 fixation reactions[9] to the direct synthesis of motif
cycle and suggested the unexpected participation of Ni(I)
species in the coupling event.
A, and an unprecedented Ni-catalyzed intramolecular reductive
Heck-coupling[10,11] followed by CO2-based carboxylation was
mustered to this end.
It is worth mentioning that, although
a number of
enantioselective metal catalyzed truncated Heck-couplings
have been reported (Scheme 1a),[12] the use of CO2 as the final
“electrophilic” trapping agent of the in situ generated organo-
metallic intermediate has never been associated so far to this
methodology.
The interest in carbon dioxide in organic synthetic method-
ology as a valuable and desirable C1-synthon, is experimenting
an exponential growth.[1] Its low toxicity, abundance and
reduced cost are unquestionable “pros” supporting its use,
which usually counterbalance some major “cons” such as high-
activation barriers and low solubility in organic solvents. Over
the past decade, incredible steps towards the chemoselective
catalytic electrophilic as well as nucleophilic activation of CO2
have been taken, making the selective incorporation of CO2 in
organic scaffolds accessible in synthetically useful manners.[2]
In organic synthesis, catalytic carboxylation[3] and
carbonylation[4] protocols, based on a low-pressure CO2 atmos-
phere, represent important cornerstones in the creation of
chemical complexity/diversity via C1-homologation reactions.
However, despite the titanic efforts deployed in this direction
by means of metal-based and metal-free catalysis, the realiza-
tion of added-value compounds via enantioselective CO2-based
Figure 1. Examples of bio-active compounds featuring 2,3-dihydrobenzofur-
an-3-ylacetic acid scaffold A and analogues.
[a] A. Cerveri, R. Giovanelli, D. Sella, R. Pedrazzani, Prof. M. Monari,
Prof. M. Bandini
Dipartimento di Chimica “Giacomo Ciamician”
Alma Mater Studiorum – Università di Bologna
Via Selmi 2, 40126, Bologna (Italy)
E-mail: marco.bandini@unibo.it
[b] Dr. O. Nieto Faza, Prof. C. S. López
Departamento de Química Orgánica
Universidade de Vigo
As Lagoas (Marcosende), 36310, Vigo (Spain)
E-mail: carlos.silva@uvigo.es
[c] Prof. M. Bandini
Consorzio CINMPIS
via Selmi 2, 40126, Bologna (Italy)
Scheme 1. State of the art and present working plan for the enantioselective
synthesis of the 2,3-dihydrobenzofuran scaffold.
Supporting information for this article is available on the WWW under
https://doi.org/10.1002/chem.202101082
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Table 1. Optimization reaction conditions.[a]
In this paper, we present our recent findings in the
enantioselective (ee up to 99%) tandem Heck-coupling/carbox-
ylation protocol with CO2 by means of an air stable and fully
characterized chiral NiÀ pyridyl imidazolyl pre-catalyst. The
reaction mechanism has been addressed through a combina-
tion of experimental and computational studies, enabling what
is proposed to be a Ni(I)-assisted truncated Heck-coupling
event, along with a stereodiscrimination model based of non-
covalent interactions at the stereo-determining transition
states.
At the outset of the investigation, we envisioned that
iodoÀ arylether 1a could act as a suitable model acyclic
precursor to yield the desired dihydrobenzofuran-3-ylacetic acid
scaffold under reductive cross-coupling/carboxylative condi-
tions. Targeting abundant and low toxic 3d-TMs as catalysts,
nickel complexes were assessed along with a survey of reaction
parameters. Delightfully, the use of the in situ formed L3/NiI2
(20/10 mol%) pre-catalyst, Zn (3 eq) as reducing agent, TMSCl
(3 eq) and TBAI (20 mol%) as additives, released the desired
benzofused acetic acid (R)-2a in 52% yield and 93% ee via
exposure to an atmosphere of CO2 in DMF (0.07 mM, rt, 16 h,
Table 1 entry 3). The main by-products i–iv (Scheme of Table 1)
were identified in variable amounts in the Ni-catalysis and
accounts for the moderate yield.
From the screening of reaction conditions, the use of C2-
symmetric chiral PyBox L1 and Box L2 ligands did not yield
synthetically useful results (entries 1,2). The introduction of an
electron-withdrawing unit into the C1-symmetric PyOx (i.e. CF3,
L4) at the C5-position of the pyridyl ring resulted in a marked
degrading of chemical outcomes (entry 4). The presence of a
mild donor with reduced steric volume (i.e. Me, L5) in proximity
to the coordinating pyridyl nitrogen atom proved not only
highly detrimental for the turnover of the process but also led
to an inversion of the stereochemical induction (see Supporting
Information for computational analysis). Modifying the tBu
steric probe on the oxazoline framework also produced
undesired effects (L6–L9). In order to test if more profound
changes to the electronic structure of the ligand would improve
the output of this process, we tested some imidazoline variants
(L10–L11). Gladly, the replacement of PyOx L3 with pyridyl
imidazoline ligand L11 (DIPP: 2,6-iPr-phenyl)[13] resulted in
substantial improvements in both reproducibility and chemical
outcomes (yield=66%, ee=96%) in the presence of NiBr2 ·DME
(entry 12). Focusing on the role of additives, the use of catalytic
amounts (20 mol%) of TBAI (tetrabutylammonium iodide)
improved the turnover of the process (yield=47%, ee=96%,
entry 16) likely facilitating the release of the metal from the
final carboxylates. Even more pronounced was found to be the
impact of TMSCl on the mechanism (entry 14): its omission
caused complete inhibition of the process. This can be
attributed to multiple actions such as: i) activation of the metal
powder reductant; ii) co-activation of the CO2 and iii) metal
scavenging of the final carboxylates. Room temperature led to
Run
Conditions
Yield 2a [%][b]
Ee 2a [%][c]
1
2
3
4
5
6
7
8
L1
L2
L3
L4
L5
L6
L7
L8
traces
13
52
Traces
8
18
Traces
30
11
36
58
66
60
NR
NR
47
31
14
ND
-21[d]
93
ND[e]
À 7
41
ND
71
9
L9
L10
L11
À 72[d]
10
11
12
13
14
15
16
17[f]
18[g]
19
20
90
96
96
93
–
–
96
98
95
L11/NiBr2 ·DME
L11/NiCl2 ·glyme
No TMSCl
No CO2
No TBAI
°
0 C
°
60 C
Mn instead of Zn
traces
43
ND
97
Br-1a was used
[a] Reaction conditions: 1a (0.07 M). Under anhydrous conditions. [b]
Determined after flash chromatography. [c] Determined via chiral HPLC.
The absolute configuration of 2a was determined via X-Ray analysis (vide
infra). [d] Inverted stereoinduction was observed. nr: no reaction. nd: not
determined. [e] By-products derived from dehalogenation, rearrangement
and dimerization of de-iodinated 1a were isolated as major outcomes. [f]
By-product III (ref [12]) was isolated in 56% yield. [g] Substantial
decomposition of the starting material was recorded. DME: dimeth-
oxyethane.
ORCID (Carlos Silva Lopez) https://orcid.org/0000-0003-4955-9844
expense of a light decrease in the chemical yield (yield=43%,
ee=97%, entry 20).
In an attempt to simplify the protocol and in order to get
further insight into the real nature of the catalytically active
chiral Ni complex, we envisioned the possibility of using a pre-
formed Ni-adduct in the carboxylation event. Here, the syn-
thesis of L11À NiCl2 was attempted by refluxing in THF a 2:1
mixture of L11 and dried NiCl2. Interestingly, a single-crystal X-
ray study carried out on one crystal grown from the resulting
pale-green solid revealed the formation of the cationic aquo
complex [(L11)2Ni(H2O)Cl]+(ClÀ as counterion). The Ni(II) center
exhibits a distorted octahedral geometry (Figure 2a, Figure S2)
°
°
optimal results with respect to 0 C or 60 C (entries 17,18) and
Zn as a stoichiometric sacrificial metal reductant proved
superior to Mn (entry 19). Finally, the bromo derivative Br-1a
could also be employed as a model substrate, although at the
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Interestingly, this cationic aquo complex [(L11)2Ni(H2O)Cl]Cl
(5–10 mol%) proved high competence in promoting the
carboxylative truncated Heck-coupling of 1a delivering the
dihydrobenzofuran 2a in similar extent to the in situ approach
(Figure 2b vs entry 13, Table 1).
Having established the optimal reaction conditions, the
generality of the enantioselective carboxylative Heck cross-
coupling was assessed by subjecting a range of diversely
functionalized ortho-aryliodines (1b–s) to the cascade protocol
in the presence of [(L11)2Ni(H2O)Cl]Cl (10 mol%). The chemical
outcomes of these essays have been collected in Scheme 2a–d
and from the results some preliminary conclusions can be
drawn.
Figure 2. Synthesis of aquo [(L11)2Ni(H2O)Cl]Cl adduct and employment in
the enantioselective carboxylative Heck-coupling.
Tolerance towards decoration of the phenolic ring with
electron-donating substituents (Me, iPr, tBu) was recorded
through substrates 1b–j. In particular, the corresponding 2,3-
dihydrobenzofuran-3-ylacetic acids 2b–j were isolated in
synthetically useful yields (61–69%) and enantiomeric excesses
systematically higher than 90% were obtained (Scheme 2a/b).
On the contrary, limitations of the method emerged from the
accommodation of EWGs at the aromatic ring (i.e. 4-Cl, 4-CF3)
that led to the direct carboxylation of the benzene ring,
prevalently.[14]
The possibility to decorate the newly formed all carbon
quaternary stereogenic centers with different substituents was
then considered (Scheme 2c). In particular, aliphatic, aromatic
and OMe groups were successfully installed at different
distances from the stereocenter (2k–o) resulting in similar and
remarkable chemical and optical outcomes (ee up to 98%).
Finally, the role of the tethering unit was investigated by
being coordinated by one chloride, one H2O molecule and two
pairs of N atoms of the bidentate L11 ligand. The ClÀ and H2O
ligands are in mutual cis position whereas in the bidentate N N
ligands (L11) the pyridyl N atoms adopt a trans arrangement
and the imidazolyl N atoms have a cis disposition.
The NiÀ Npy distances [2.073 and 2.084(3) Å] are similar and
shorter than the NiÀ Nim ones [2.092 and 2.122(3) Å] being the
latter N atom positioned trans to the chloride ligand. The NiÀ O
and NiÀ Cl distances [2.126 and 2.141(3) Å] fall in the range
typical for Ni complexes. The NpyÀ NiÀ Nim bite angles in the two
five-membered metallacycles are almost identical [78.4(2) and
°
77.8(1) , respectively]. The pyridyl and imidazoline rings in each
L11 ligand are not coplanar but have dihedral angles of 18.2
°
and 17.7(2) , respectively, due to steric congestion generated
by the bulky substituents.
Scheme 2. Substrate scope of the present Heck-carboxylation cascade reaction (a–d). Absolute configuration determination (e) and labelling isotopic
experiment (f).
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replacing the oxygen atom with C- as well as N-based
connectors (2p–s, Scheme 2d). Here, although N-allyl- and N-
Boc-indoline scaffolds 2p–r were isolated in moderate extents
(ee: 11–69%), the enantio-enriched dihydroindene acetic acid
2s was obtained in excellent stereochemical yield (ee=98%).
Then, the absolute configuration of compound 2a was
unambiguously determined to be R via single crystal X-ray
analysis of the corresponding bromo-amide 3a (Scheme 2e).
Additionally, the pivotal role of CO2 in generating the carboxylic
unit of targeted compounds 2 was determined via a labelled
13C-experiment. As a matter of fact, a full incorporation of
13CÀ carbon dioxide (99.8% labelling) was obtained in the final
compound 2a when 13CO2 was employed under optimal
reaction conditions (13C-2a, yield=65%, ee=98%, Scheme 2f).
In order to gain further insight into this reaction, a
mechanistic exploration was carried out in parallel by DFT
simulations (detailed methodology can be found in the
Supporting Information).[15] Several questions that are key to
the understanding of this reactivity are, at least: 1- what is the
structural model of enantiodiscrimination, 2- which is the active
catalyst and 3- how the fundamental role of the solvent can be
explained.[16]
Initially we assumed that the [(L)2Ni(H2O)Cl]Cl complex, with
a 2:1 L:Ni ratio, would dissociate delivering the LNi species I as
the active catalyst (see the NLE experiment).[17] We also assumed
that [Ni(0)] would be the oxidation state of the catalyst, after
reduction with the excess of zinc.[18] Catalytic cycles were
simulated via DFT calculations (for computational details see
the Supporting Information) for the PyOx (L3) and its imidazo-
line variant L11. Both ligands yielded similar reaction profiles.
First we explored a [Ni(0)]/[Ni(II)] catalytic cycle in which Zn
would only participate at the end, to restore the active [Ni(0)]
catalyst I (path A – red zone in Scheme 3). From this, a facile
oxidative addition of 1a occurs to form intermediate II. Then,
the stereodiscriminating addition of the NiÀ C bond to the
alkene must occur. The barriers associated to the formation of
the two diastereomers favor (by 2.5 kcal/mol) the formation of
intermediate III. We attempted to describe this step also on the
neutral complex II but we could only find the associated
transition state assuming prior loss of iodine. This is explained
through the need to open a coordinating vacant site such that
the double bond can be pre-activated for the addition step.
However, the insertion of CO2 onto intermediates III and III-
diast, to yield the final carboxylates IV and IV-diast, featured
high activation energies (26.3 and 36.7 kcal/mol, respectively)
rendering these paths unlikely.
We therefore decided to analyze whether a zinc-mediated
[Ni(II)]/[Ni(I)] reduction step along the reaction pathway could
facilitate the carboxylation event,[19] and indeed, the reaction
proceeds much more favorably if Ni is reduced right before CO2
insertion (path B – yellow block in Scheme 3). This reduction
step could also be occurring earlier in the mechanism, right
after the oxidative addition (path C – yellow block in Scheme 3).
Interestingly the latter alternative, which involves a rare Heck
step occurring at a Ni(I) species, also produces very competitive
barriers for the subsequent steps.
Scheme 3. Reaction mechanism explored via density functional theory. A
relative-free-energies computed at the PCM(DMF)-M06/Def2SVPP level of
theory at 1 atm and 298 K. See the Supporting Information for simulation
details.
To be able to determine which, of these two alternative
pathways (B or C), is more plausible and at what point along
the mechanism the reduction step is operating, we analyzed
our experimental results in detail. While doing so we realized
that one very common side product of this protocol is the
benzoic acid derivative (SP)[14] deriving by a direct carboxylation
of the arylÀ Ni intermediates. We therefore computed the
transition state for this carboxylation both at the [Ni(II)] and
[Ni(I)] complexes. We found that this step is very costly for the
[Ni(II)] complex (a computed barrier of about 30 kcal/mol) and
that it is feasible when acting on the [Ni(I)] species.[18] These
results therefore not only help explain the formation of this
byproduct but also strongly candidate the path B – yellow block
in Scheme 3 as the mechanism at work, involving an unusual
Heck step on a [Ni(I)] complex.[20]
In an attempt to unequivocally determine the nature of the
active catalyst, we performed a non-linear effect study[17] on the
model transformation 1a!2a, by varying the enantiopurity of
the chiral ligand L3. Interestingly, a perfect linear correlation
between ee(L3) and ee(2a) was observed (see Figure S1).
This finding led us to conclude that indeed the isolated
[(L11)2Ni(H2O)Cl]Cl species should be considered a pre-catalytic
unit, capable of delivering the active 1:1 active organometallic
species through an in situ ligand dissociation event.
Non-covalent interactions (NCI) analysis performed onto
transition states TSII–III and TSII–IIIdiast provides an interesting
picture of the stereodiscriminating mechanism where the tBu
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group location is pivotal to differentiate between the two Conflict of Interest
available trajectories for the cyclization (Figure 3). In both cases
there is steric contact with this group, however, it is consid-
erably stronger in the Ω trajectory than in the U alternative. In
the former the tBu group is pushed back by the incoming
alkene which also translates into stronger steric contacts with
the heterocyclic fragment of the chiral ligand in the back.
The strong impact of a methyl group in L5 (Table 1, entry 5)
was also diagnosed via NCI analysis and the crucial role of the
solvent (i.e. DMF) on CO2 activation was explained through a
DFT model as well. Detailed answers to these points are
provided in the Supporting Information.
In conclusion, an enantioselective nickel catalyzed tandem
Heck-coupling/CO2-carboxylation reaction has been reported
and its scope was evaluated to be wide enough to provide an
unprecedented and versatile protocol for the synthesis of
stereodefined hetero-benzofused acetic acids. A fully elucidated
mechanistic profile, comprising an unusual Ni(I)-mediated Heck-
type elementary step, was also proposed based on a combined
experimental/computational analysis. Attempts to extend the
present organometallic enantioselective strategy to the con-
struction of differently and densely functionalized carboxylic
acid derivatives through CO2 fixation are underway in our
laboratory and the results will be documented in due course.
The authors declare no conflict of interest.
Keywords: asymmetric catalysis
carboxylation · cross-coupling · nickel
·
carbon dioxide
·
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Experimental Section
Crystallographic data: Deposition numbers 2057596, and 2057597
contain the supplementary crystallographic data for this paper.
These data are provided free of charge by the joint Cambridge
Crystallographic Data Centre and Fachinformationszentrum Karls-
ruhe Access Structures service.
Acknowledgements
University of Bologna is kindly acknowledged for the financial
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to the double bond.
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Communication
doi.org/10.1002/chem.202101082
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Manuscript received: March 25, 2021
Accepted manuscript online: April 7, 2021
Version of record online: ■■■, ■■■■
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COMMUNICATION
A. Cerveri, R. Giovanelli, D. Sella, R. Pe-
drazzani, Prof. M. Monari, Dr. O.
Nieto Faza, Prof. C. S. López*, Prof. M.
Bandini*
1 – 7
COTWO task. An enantioselective
nickel catalyzed tandem Heck
coupling/carboxylation synthetic
sequence with CO2 is reported that
provides ready access to 2,3-dihydro-
benzofuran-3-ylacetic acids and
analogous compounds (ee up to
99%). Labelling experiments, DFT
analysis and X-ray characterizations
enabled both mechanistic steps and
stereodiscriminating transition states
to be fully elucidated.
Enantioselective CO2 Fixation Via a
Heck-Coupling/Carboxylation
Cascade Catalyzed by Nickel